ACC is a malignant neoplasm that arises within the secretory glands, most commonly in the salivary glands of the head and neck, and is characterized by slow and unpredictable growth that is often fatal. ACC has a propensity to spread along nerve fibers and metastasize to other locations in the body. Recurrent MYB translocations have been identified in the majority of ACCs, which are characterized by overexpression of MYB and MYB targets. MYB is a master transcription factor with roles in proliferation and differentiation, and many of the ACC translocations involve another transcription factor, NFIB. Alterations in MYB have been implicated in a variety of cancers, including leukemia, pediatric gliomas, and cancers of the colon, breast and prostate. ACC-specific MYB translocations have been recently shown to promote transformation in genetically engineered mouse models.
Despite aggressive multimodality management, approximately half of ACC patients develop distant metastases, and up to one-third die within two years of diagnosis. No standard systemic chemotherapy regimen or approved drug therapy exists for recurrent or metastatic ACC, and no drug therapy has demonstrated either survival or progression-free survival benefit. Whole-exome sequencing of ACC tumors has revealed mutations in NOTCH and fibroblast growth factor signaling and chromatin remodeling genes, which could serve as potential therapeutic targets. However, over 30 phase II clinical trials since 1985 involving cytotoxic therapy or targeted therapies against c-Kit, epidermal growth factor receptor, fibroblast growth factor receptor, and mammalian target of rapamycin, among others, have not been successful. Activating NOTCH1 mutations occur in about 15% of ACCs, limiting the therapeutic use of Notch inhibitors. Hence, targeting MYB represents a desperately needed therapeutic strategy that has the potential to elicit broad clinical activity across many ACC tumors.